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Prolonged Postnatal Hypoxia Impairs Lung Development and Causes Severe Pulmonary Hypertension in Mice
Luca Zazzeron1, Kakeru Shimoda1, Paul Lichtenegger1
1Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA.
Insights
This study developed a mouse model for pediatric pulmonary hypertension by exposing newborn mice to hypoxia. This model mimics lung development abnormalities and right ventricular failure seen in high-altitude-born children.
Area of Science:
- Pediatric pulmonology
- Cardiovascular research
- Hypoxia studies
Background:
- High-altitude birth impacts lung development, leading to pulmonary hypertension and right ventricular failure in children.
- Existing animal models fail to replicate these pediatric high-altitude conditions.
- A novel mouse model is needed to study pediatric pulmonary hypertension and abnormal lung development.
Purpose of the Study:
- To establish a mouse model of pediatric pulmonary hypertension.
- To investigate the effects of early-life hypoxia on lung development and cardiovascular function.
- To provide a platform for testing potential treatments.
Main Methods:
- C57bl/6J mice exposed to 11% oxygen from postnatal days 1-4.
- Assessed pulmonary arterial pressure and right ventricular function via echocardiography and invasive hemodynamics at 8 weeks.
- Evaluated lung structure, gas exchange, and respiratory mechanics; compared with controls and adult hypoxic mice.
Main Results:
- Early-life hypoxia led to impaired lung development (alveolar/vascular simplification, vessel muscularization) in surviving mice.
- Mice exhibited severe pulmonary hypertension, right ventricular failure, reduced exercise capacity, and impaired gas exchange.
- Adult hypoxia caused mild pulmonary hypertension without right ventricular dysfunction.
Conclusions:
- This model effectively replicates key features of pediatric pulmonary hypertension associated with abnormal lung development.
- It offers a valuable tool for understanding disease mechanisms and developing therapeutic strategies.
- The model highlights the critical impact of early-life hypoxia on lung and cardiovascular health.
Background:
In children born at high altitude, lung development is affected by hypoxia, which can lead to pulmonary hypertension and right ventricular failure. Animal models of postnatal, transient, hypoxia failed to reproduce these conditions seen in children living at high altitude. The aim of this study was to establish a mouse model of pediatric pulmonary hypertension associated with abnormal lung development.
Methods:
C57bl/6J mice were exposed to normobaric hypoxia at 11% inspired fraction of oxygen starting on postnatal-days 1 to 4 ("11%-birth"). At age 8 weeks, pulmonary arterial pressure and right ventricular function were assessed using echocardiography and invasive hemodynamics. The physiology and the structure of lung parenchyma and vasculature were assessed through evaluations of gas exchange, respiratory mechanics, and histopathology. Results were compared with control mice breathing 21% inspired fraction of oxygen for 8 weeks (21%-birth), and to adult mice breathing 11% inspired fraction of oxygen for 8 weeks (11%-adult).
Results:
Seventy percent of 11%-birth mice survived until age 8 weeks; the mice subsequently experienced a steady decline in survival, with a median lifespan of 150 days. Mice that survived for 8 weeks had evidence of impaired lung development, such as alveolar and vascular simplification with muscularization of small pulmonary vessels, impaired gas exchange, and altered respiratory mechanics. These changes were associated with reduced exercise capacity, severe pulmonary hypertension, and right ventricular failure. Adult mice subjected to chronic hypoxia had mild changes in the pulmonary vasculature resulting in mild pulmonary hypertension without right ventricular dysfunction.
Conclusions:
This mouse model of prolonged hypoxia beginning early after birth offers a novel approach to explore treatments for pediatric pulmonary hypertension linked to abnormalities in lung development.
